The invention relates to inhibiting specific receptor-ligand interaction between Alzheimer's amyloid-β peptide (Aβ) and the Receptor for Advanced Glycation Endproducts (RAGE).
A number of genetic, cellular, biochemical, and animal studies suggest accumulation of amyloid β-peptide (Aβ) in the brain is the key event in Alzheimer's disease (AD), while the rest of the disease process, including formation of neurofibrillar tangles results from an imbalance between Aβ production and Aβ clearance (Hardy & Selkoe, 2002; Tanzi et al., 2004; Zlokovic, 2005). Aβ is neurotoxic (Walsh et al., 2002; Kayed et al., 2003; Gong et al., 2003) and deposits as amyloid in brain parenchyma and brain vessels in patients with sporadic AD and familial forms of AD (FAD). The mechanisms responsible for Aβ production, i.e., the proteolytic enzymes β- and γ-secretases which cleave Aβ from its larger precursor protein (APP), have been characterized (Selkoe, 1998; Vassar et al., 1999) and their respective inhibitors developed. Increased Aβ production, however, can explain only a small number of early onset FAD cases bearing inherited mutations in the APP gene (i.e., Swedish mutation) or presenilins 1 or 2 genes, but does not contribute to late-onset AD or >98% of all AD cases (Selkoe, 2001; Holtzman & Zlokovic, 2006). According to a new emerging concept, reduced Aβ clearance and/or its increased influx and re-entry into the brain from circulation via transport across the blood-brain barrier (BBB) may be responsible for Aβ brain accumulations in sporadic AD (Tanzi et al., 2004, Zlokovic, 2005; Holtzman & Zlokovic, 2006).
Recent evidence indicates that Aβ within the intravascular space is linked to deposited Aβ in the brain suggesting that transport of Aβ from blood to brain and from brain to blood across the blood-brain barrier (BBB) regulates brain Aβ (Shibata et al., 2000; De Mattos et al., 2002a; De Mattos et al., 2002b; Bading et al., 2002; Mackic et al., 2002; Carro et al., 2002; Deane et al., 2003; Deane et al., 2004; Tanzi et al., 2004; Zlokovic, 2005; Holtzman & Zlokovic, 2006). Numerous studies in animal models (reviewed by Deane et al., 2004; Holtzman & Zlokovic, 2006) and some studies in AD patients demonstrating increased levels of Aβ on plasma lipoproteins and proteins (Matsubara et al., 1999; Kuo et al., 1999), have suggested that re-entry of circulating Aβ into the brain via transport across the BBB is an important source of brain Aβ. High plasma levels of Aβ40/42 have been determined in mouse models of Aβ under basal conditions, e.g., APPsw+/− mice (Kawarabayashi et al., 2001) or after treatment with Aβ peripheral binding agents, e.g., anti-Aβ antibodies (De Mattos et al., 2002a), sRAGE (Deane et al., 2003), which confirms the link between intravascular and brain Aβ.
RAGE is a multiligand receptor in the immunoglobulin superfamily which binds a broad repertoire of ligands including Aβ (Stern et al., 2002). In mature animals there is relatively little expression of RAGE in most tissues, whereas deposition of ligands triggers RAGE expression. When Aβ accumulates in AD or in animal models of AD, RAGE expression increases particularly in cerebral microvessels, a site of the BBB in vivo (Yan et al., 1996; Deane et al., 2003; LaRue et al., 2004; Donahue et al., 2004). RAGE binds soluble Aβ in the nano-molar range, and mediates pathophysiologic cellular responses consequent to ligation by Aβ (Yan et al., 1996; Mackic et al., 1998; Yan et al., 2000). These include transport of pathophysiologically relevant concentrations of plasma Aβ across the BBB, neurovascular stress, and reduction in the cerebral blood flow (CBF) (Deane et al., 2003; LaRue et al., 2004). Deletion of the RAGE gene protects the CNS pool of Aβ from influences of its peripheral pool by eliminating re-entry of circulating Aβ into the brain, whereas systemic treatment with soluble RAGE (sRAGE) sequesters circulating Aβ and reduces brain accumulation and deposition of Aβ in a mouse model of AD (Deane et al., 2003). Thus, compounds which block Aβ/RAGE interaction at the BBB may also block re-entry of Aβ to the brain, reduce Aβ-related pathology, and improve CBF dysregulation and cognitive decline, which should have important beneficial therapeutic effects in AD.
Compounds to inhibit Aβ/RAGE interaction, compositions containing one or more of those compounds, and methods of treatment are taught herein to be applicable to Alzheimer's disease and other conditions involving Aβ-RAGE interaction at the blood-brain barrier, RAGE-mediated transport of Aβ into the brain, and/or RAGE activation RAGE activation in brain vasculature or brain parenchyma. Other advantages of the invention are discussed below or would be apparent to a person skilled in the art from that discussion.